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Case Report

doi: 10.5606/tjr.2012.047

Turk J Rheumatol 2012;27(4):262-266

Chronic Recurrent Multifocal Osteomyelitis:Treatment with a Tumor Necrosis Factor-Alpha Inhibitor

Kronik Tekrarlayan Multifokal Osteomiyelit: Tmr Nekroz Faktr-Alfa nhibitr Tedavisi

Andr de Souza CAVALCANTI, Evaldo Gomes SENA, Srgio Vasconcelos CAVALCANTI,

Fernando de Souza CAVALCANTI, ngela Luzia Branco Pinto DUARTE

Federal University of Pernambuco, Department of Clinical Medicine, Recife, Pernambuco, Brazil

Received:February 14, 2012 Accepted:May 18, 2012

Correspondence:Fernando de Souza Cavalcanti, M.D. Universidade Federal de Pernambuco, Medicina Clinica, Recife/Pernambuco, Brazil. Tel: 55 81 3454.0155 e-mail: [email protected]

2012 Turkish League Against Rheumatism. All rights reserved.

Bakteriyel olmayan osteit (NBO) olan kronik tekrarlayanmultifokal osteomiyelit (CRMO), nadir grlenotoinflamatuvar immn bozukluudur. Hastaln tansndagecikme, iskelet sisteminde geri dn olmayan hasara yolaabilir. Kronik tekrarlayan multifokal osteomiyelit, Majeedsendromu ve farelerde kronik multifokal osteomiyelit(CMO) arasndaki benzerlikler, kuvvetli bir ekilde genetikzemine iaret etmektedir. Bu yazda konvansiyonel tedavibaarszlkla sonulandktan sonra, tmr nekroz faktr-alfa (TNF-a) inhibitr ile baarl bir ekilde tedavi edilen10 yanda bir erkek CRMO olgusu sunuldu. Be yl

akn bir sreyle hastann eklemlerinde aralklarla arseyrediyordu ve hasta nonsteroid antiinflamatuvar ilalar(NSA) ile tedavi edildi. Semptomlarn nedenini aratrmakzere, hasta pediatri ve ortopedi servisine yatrld, septikosteomiyelit tans kondu. eitli antibiyotikler ile tedaviedildi, ancak durumunda hibir iyileme grlmeyince,hasta bir pediatrik romatoloji uzmanna sevk edildi. Buolgunun tansnda manyetik rezonans grntleme (MRG)ve rntgen ok nemliydi. Bu olgu, CRMO phesi tayanhastalarda kemik hasarn nlemek ve yeterli dzeydetedavi salamak iin hzl sevk ihtiyacn vurgulamak iinbir rnek tekil etmektedir.

Anahtar szckler: Kronik tekrarlayan multifokal osteomiyelit;bakteriyel olmayan osteoit; tmr nekroz faktr.

Chronic recurrent multifocal osteomyelitis (CRMO), anon-bacterial osteitis (NBO), is a rare auto-inflammatoryimmune disorder. A delay in the diagnosis of this diseasemay cause irreversible damage to the skeletal system.The similarities among CRMO, Majeed syndrome, andchronic multifocal osteomyelitis (CMO) in mice stronglyindicate a genetic basis. In this article, we present a10-year-old boy with CRMO who was successfully treatedwith a tumor necrosis factor-alpha (TNF-a) inhibitor afterconventional management had failed. Over a five-yearperiod, he had experienced intermittent pain in his joints

and been treated with non-steroidal anti-inflammatorydrugs (NSAIDs). In a search for the cause of thesesymptoms, he was admitted to a pediatric or thopedic unitwhere he was diagnosed as having septic osteomyelitis.He underwent treatment with several antibiotics, howeverno improvement was seen and he was referred to apediatric rheumatologist. Magnetic resonance imaging(MRI) and X-rays were crucial in the patients diagnosis.This case serves as an example of the need to emphasizeprompt referrals for patients suspected of having CRMOso as to avoid bone damage and provide adequatemanagement.

Key words: Chronic recurrent multifocal osteomyelitis; non-bacterial osteitis; tumor necrosis factor.

Chronic recurrent multifocal osteomyelitis (CRMO)is an autoinflammatory, autosomal-recessive immunedisease that was first described in 1972. It has a female tomale ratio of 4:1, and 260 cases have been reported.[1]Thisdisease is characterized by bone pain and fever causedby non-infectious agents, and it has a course of recurrentflare-ups followed by spontaneous remissions.[1,2]

Chronic recurrent multifocal osteomyelitis is consideredthe pediatric version of the synovitis, acne, pustulosis,hyperostosis, osteitis (SAPHO) syndrome.[3]

The etiology of CRMO remains unclear. It is knownthat infections, immune deficiency, and autoimmunityare unlikely causes. The similarity with Majeedsyndrome, an autosomal disorder,[4] and chronic


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263Chronic Recurrent Multifocal Osteomyelitis

multifocal osteomyelitis (CMO) in mice,[5]

suggests agenetic origin. Mutations in LPIN2 cause a syndromicform of CRMO, and mutations in proline-serine-threonine phosphatase interacting protein 2 (PSTPIP2)cause a murine form of the disorder.[4,5]

It is unclear how best to manage CRMO as therehave been few randomized trials. Non-steroidal anti-inflammatory drugs (NSAIDs) are considered to bethe first line of therapy. Corticosteroids have alsobeen utilized with relative success; however, their sideeffects limit their use. In addition, disease-modifying

antirheumatic drugs (DMARDs), especially those

with steroids, have been prescribed for patients withmore severe manifestations.[6] We report the use of atumor necrosis factor-alpha (TNF-) inhibitor in apatient unresponsive to other treatments who had beensuffering from CRMO.

CASE REPORT

A 10-year-old boy was referred to the PediatricRheumatology Unit at the University Hospital Federal

University of Pernambuco, Recife in 2008 with a five-year history of intermittent pain in his left clavicle,right hip, ankles, and dorsal spine. In 2006, he wasadmitted to the Pediatric Unit complaining of backpain, fever, and a mass over his left clavicle. Blood testsshowed a C-reactive protein (CRP) level of 24 mg/dl andan erythrocyte sedimentation rate (ESR) of 39 mm/h.A chest X-ray confirmed the mass over his left clavicle(Figure 1). Septic osteomyelitis was diagnosed, althoughhis blood and bone cultures were negative. A course ofan empirical antibiotic (cephalothin) and NSAIDs

was prescribed. He was later referred (after one year)to the Orthopedic Unit where a thoracic computedtomography (CT) scan showed the volume of the leftclavicle had increased due to an area of hyperostosismixed with osteolysis. Hence, the antibiotic waschanged to ciprofloxacin for three months. As therewas no improvement, he was referred to the PediatricRheumatology Unit, where a tuberculin test and ANAwere negative. A bone scan showed an increasedtechnetium-99m (99mTc) radioisotope uptake at theleft clavicle, ankle, sacroiliac joints, and T8 thoracicdisc (Figure 2). Magnetic resonance imaging (MRI)demonstrated multiple inflammatory lesions betweenthe T7and T9disks (Figure 3) and in the left clavicle

Figure 1.A chest X-ray showed bone enlargement on the leftclavicle.

Figure 2. A bone scan (technetium-99m) revealed anincreased uptake on the left clavicle, thoracic spine, sacroiliac

joints, and left ankle.

Figure 3. A thoracic magnetic resonance imagingshowed inflammatory bone lesions on T7-T9.


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and left ankle (Figure 4), thus confirming the findingson the bone scan and thorax CT. The results of the

histological analysis of a bone biopsy were compatiblewith aseptic chronic osteomyelitis (Figure 5). Noinfection was identified by lesion or blood culture,and no malignancy was detected by imaging; hence,the possibility of CRMO was raised. An aggressivetreatment with NSAIDs, alendronate 70 mg/week,methotrexate 15 mg/week, and inf liximab 5 mg/kg wasinitiated due to the severity of the case and the delay indiagnosis. After the third infusion of infliximab, theboy became free of pain. His ESR and CRP levels werenormal, and a bone scan showed a tiny uptake at the

left clavicle. It should be noted that the patient and hisfamily gave their consent for any treatment provided atthe Pediatric Rheumatology Unit.

The patient is now doing well and growing at anormal rate. This report emphasizes the importanceof referring children with unexplained joint painand fever to a pediatric rheumatologist for an earlydiagnosis so that appropriate treatment can begin assoon as possible.

DISCUSSION

Having sterile bone lesions with non-specific signsof inflammation is a feature shared by several

disorders.[1]They are recurrent in nature[4]and are oftenassociated with comorbid inflammatory disorders.[1,2,4,7]Involvement of other organs has been reported;[8,9]

however, in this case, the simultaneous bouts of painwere restricted to multiple bone locations: the pelvis,

clavicle, vertebrae, and both legs. Eighty-five percentof the CRMO cases have occurred in girls with amedian onset age of 10 years old. The most commonmanifestations are fever accompanied by bone pain andsigns of inflammation in the soft tissues around theborder of the affected regions.[1,2] The early literaturesuggested CRMO was self-limiting in most cases but thatit could last as long as 15 years.[2]At present, the medianduration of activity is 2.7 years, and the median timebetween the first symptom and diagnosis is 9.2 months(range, 1-26 months).[7]In this case, there was a five-year

delay before a definitive diagnosis was made.Elevated TNF- (>25 pg/ml) occurs in 66% of

cases of CRMO,[1] and an increase in acute phaseprotein[1,2]suggests a flare-up. Blood and bone culturesare negative, including tests for mycobacterium andmycoplasma.[10] Our patient had a slight increase inESR, negative blood and bone marrow cultures, and anegative test for tuberculosis.

An X-ray can show areas of osteolysis at themetaphysis and diaphysis as well as the sclerosis aroundit.[10,11]Bone scans (99mTc), CT, and MRIs can help inthe diagnosis by determining the location for a bonebiopsy and assessing the activity of the disease.[11]The

Figure 4.A left leg magnetic resonance imagingdemonstrated osteolytic lesion changes on theleft distal tibial metaphysis.

Figure 5.Foreign body granuloma (H-E x 10).


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265Chronic Recurrent Multifocal Osteomyelitis

X-ray and MRI images were of great importance in ourcase since they provided evidence of the osteolysis andbone enlargement lesions.[12,13] Vertebral compressionis a rare radiographic finding, but an MRI revealed

compressive lesions of the spine at T7-T9 along withscoliosis in our patient. His pain was lessened after hewas treated with NSAIDs.

No similarity exists between CRMO andtuberculous spondylitis, in which infection begins onthe anterior parts of vertebral bodies and progresses tothe intervertebral disc. Areas of bone destruction arewell defined in tubercular spondylitis, and a paraspinalabscess is formed that may extend to the psoas muscle.

A bone biopsy is necessary for the differentialdiagnosis of CRMO in order to exclude malignancyand infection, and pyogenic osteomyelitis, if found, isa reliable indicator of this disease. Usually an extensivemicrobial investigation (including tissue culture andserology) should be conducted since treatment withantibiotics is ineffective. However, improvement inpatients treated with azithromycin has been reported,but this can be attributed to its anti-inflammatoryeffect.[14]The biopsy of the clavicle in our case showeda chronic inflammatory reaction like that of a foreignbody granuloma.

Little is known about the function of the geneLPIN2[4] in Majeed syndrome, but its mutations couldlead to the production of more pro-inflammatorysignals. In turn, this disrupts the genes function inself-regulating oxidative stress (OS), leading to anauto-inflammatory process with tissue damage.[4]Thisdefect affects the innate immune system due to thedysregulation of a pathway that is important in boneand skin inflammation.[5]

The empirical diagnostic criteria for CRMOincludes the following: multifocal bone lesions, aclinical course extended for months with remissionsand exacerbations, a lack of response to antimicrobialtreatment, and osteolytic-sclerotic bone lesions onX-ray.[10]Compliance with all of the criteria is requiredfor a definitive diagnosis.[10]Jansonn et al.[1]undertooka retrospective analysis of 89 patients and drew updiagnostic criteria for non-bacterial osteitis (NBO), butthese have not yet been validated.

There is no specific treatment for CRMO, althoughthe symptoms usually regress with NSAIDs with80% efficacy.[6,13] Physical therapy of the impairedsegment should be considered as soon as possible.Corticosteroids have been used in multifocal relapsingcases, and improvement was seen.[15]Interferon- and

have been used in a few patients with CRMO, andsome improvement was noted. Bisphosphonates havealso used, especially pamidronate[16]since it has anti-resorptive and anti-inflammatory actions. Progress

has also been attained with the use of TNF- blockerssuch as infliximab which reportedly promoteshealing in the inflammatory lesion.[1] Although thestudy involving TNF- was not placebo-controlled,sufficient evidence still exists to justify the use ofbisphosphonates and TNF- blockers[1] in for thetreatment of CRMO when the use of NSAIDs andsteroids has failed.

In this case, the boys condition partiallyresponded to the use of NSAIDs. However,with a view toward discovering a more effective

management approach, a combination of inf liximab,which was employed in a similar manner to how it isused in the treatment of rheumatoid arthritis (RA),and alendronate was started. Methotrexate was alsoprescribed to prevent antibodies against infliximab,.Unfortunately, the small number of clinical trialsinvolving CRMO limits the use of new managementapproaches.

A follow-up study on 23 children with CRMOover a five-year period showed that most were ableto complete their schooling, get jobs, and have some

emotional stability.[17]However, CRMO is not a benigndisease, and numerous bone sequels, such as growthretardation, thoracic scoliosis, and bone deformities,have been seen.

Although in this case there were no bone sequelaeor growing defect, more clinical trials are neededto further investigate CRMO. Perhaps with furtherresearch, new treatment methods can be put intopractice to reduce the effects of this disease.

Declaration of conflicting interests

The authors declared no conflicts of interest withrespect to the authorship and/or publication of thisarticle.

Funding

The authors received no financial support for theresearch and/or authorship of this article.

REFERENCES

1. Jansson A, Renner ED, Ramser J, Mayer A, Haban M,Meindl A, et al. Classification of non-bacterial osteitis:

retrospective study of clinical, immunological andgenetic aspects in 89 patients. Rheumatology (Oxford)2007;46:154-60.


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2. Catalano-Pons C, Comte A, Wipff J, Quartier P, FayeA, Gendrel D, et al. Clinical outcome in children withchronic recurrent multifocal osteomyelitis. Rheumatology(Oxford) 2008;47:1397-9.

3. Kahn MF. Current status of the SAPHO syndrome. PresseMed 1995;24:338-40. [Abstract]

4. Al-Mosawi ZS, Al-Saad KK, Ijadi-Maghsoodi R, El-ShantiHI, Ferguson PJ. A splice site mutation confirms the role ofLPIN2 in Majeed syndrome. Arthritis Rheum 2007;56:960-4.

5. Chitu V, Ferguson PJ, de Bruijn R, Schlueter AJ, OchoaLA, Waldschmidt TJ, et a l. Primed innate immunity leadsto auto-inflammatory disease in PSTPIP2-deficient cmomice. Blood 2009;114:2497-505.

6. Girschick HJ, Raab P, Surbaum S, Trusen A, Kirschner S,Schneider P, et al. Chronic non-bacterial osteomyelitis inchildren. Ann Rheum Dis 2005;64:279-85.

7. Kerem E, Manson D, Laxer RM, Levison H, Reilly BJ.

Pulmonary association in a case of chronic recurrentmultifocal osteomyelitis. Pediatr Pulmonol 1989;7:55-8.8. Ozbek Z, Makay B, Unsal E, Durak I, Gunes D, Anal

O, et al. Conjunctival involvement in chronic recurrentmultifocal osteomyelitis. Cornea 2008;27:117-9.

9. Schultz C, Holterhus PM, Seidel A, Jonas S, Barthel M,Kruse K, et al. Chronic recurrent multifocal osteomyelitisin children. Pediatr Infect Dis J 1999;18:1008-13.

10. Hobolth L, Nemery M, Albrectsen J, Hasbak P. Chronicrecurrent multifocal osteomyelitis demonstrated byTc-99m methylene diphosphonate bone scan. Clin NuclMed 2008;33:61-3.

11. Jurik AG, Egund N. MRI in chronic recurrent multifocalosteomyelitis. Skeletal Radiol 1997;26:230-8.

12. Girschick HJ, Krauspe R, Tschammler A, HuppertzHI. Chronic recurrent osteomyelitis with clavicular

involvement in children: d iagnostic value of d ifferentimaging techniques and therapy with non-steroidalanti-inflammatory drugs. Eur J Pediatr 1998;157:28-33.

13. Schil ling F, Wagner AD. Azithromycin: an anti-inflammatory effect in chronic recurrent multifocalosteomyelitis? A preliminary report. Z Rheumatol2000;59:352-3. [Abstract]

14. Girschick HJ, Zimmer C, Klaus G, Darge K, Dick A,Morbach H. Chronic recurrent multifocal osteomyelitis:what is it and how should it be treated? Nat Clin PractRheumatol 2007;3:733-8.

15. Ishikawa-Nakayama K, Sugiyama E, Sawazaki S, TakiH, Kobayashi M, Koizumi F, et al. Chronic recurrentmultifocal osteomyelitis showing ma rked improvementwith corticosteroid treatment. J Rheumatol2000;27:1318-9.

16. Simm PJ, Allen RC, Zacharin MR. Bisphosphonatetreatment in chronic recurrent multifocal osteomyelitis.J Pediatr 2008;152:571-5.

17. Huber AM, Lam PY, Duffy CM, Yeung RS, Ditchf ield M,Laxer D, et al. Chronic recurrent multifocal osteomyelitis:clinical outcomes after more than five years of follow-up.J Pediatr 2002;141:198-203.

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